Influenza is an acute infectious disease caused by an influenza virus, and has been known to allow global pandemic threats to emerge every year. Influenza viruses infect host cells by incorporation of hemagglutinin that is a protein present on the surface of virus particles into host cells via binding to a glycoprotein on the surface of the host cells, followed by proliferation in the host cells, and subsequently the viruses are secreted out of the cells and infect another host cells.
When thus proliferated influenza viruses in host cells are secreted out of the cells, glycoproteins present on the cell surface of the host cells form complexes with hemagglutinin present on the surface of the virus particles. For releasing the virus particles from the host cells to infect other host cells, it is necessary to cleave binding between the glycoprotein and hemagglutinin, and the cleavage of this binding is carried out by neuraminidase present on the surface of the virus particles.
Oseltamivir phosphate has been known to inhibit the activity of neuraminidase, and has been used as a specific medicine for influenza. Oseltamivir phosphate has been conventionally synthesized by way of semisynthesis using shikimic acid, which is a natural substance, as a starting material (for example, see Nonpatent Document 1). However, stable supply may be difficult since the starting material is a natural substance, and thus development of a synthetic method carried out by total synthesis without using a natural substance has been demanded.
In this regard, as an intermediate for synthesizing oseltamivir phosphate by total synthesis, Patent Document 1 discloses an intermediate for producing oseltamivir phosphate, i.e., a precursor to oseltamivir phosphate, synthesized by employing a Diels-Alder reaction. In addition, Nonpatent Document 1 discloses a process for synthesizing oseltamivir phosphate using as a starting material a shikimic acid which is isolated from a natural product. Nonpatent Document 2 discloses a process for synthesizing oseltamivir phosphate starting from a dissymmetric asymmetric Diels-Alder reaction in which oxazaborolidine is utilized as an asymmetric catalyst. Nonpatent Document 3 discloses a process for synthesizing oseltamivir phosphate in which an asymmetric ring-opening reaction of a mesoaziridine ring catalyzed by an yttrium catalyst is used. Nonpatent Document 4 discloses a process for synthesizing oseltamivir phosphate starting from a dissymmetric asymmetric Diels-Alder reaction of a dihydropyridine derivative derived from pyridine. Furthermore, Nonpatent Document 5 discloses a process for synthesizing oseltamivir phosphate starting from asymmetric alkylation of an allylic position using palladium as a catalyst.
Patent Document 1: Japanese Unexamined Patent Application, Publication No. 2008-081489
Nonpatent Document 1: J. Am. Chem. Soc., vol. 119, p. 681 (1997)
Nonpatent Document 2: J. Am. Chem. Soc., vol. 128, p. 6310 (2006)
Nonpatent Document 3: J. Am. Chem. Soc., vol. 128, p. 6312 (2006)
Nonpatent Document 4: Angew. Chem. vol. 119, p. 5836 (2007); Angew. Chem. Int. Ed. vol. 46, p. 5734 (2007)
Nonpatent Document 5: Angew. Chem. vol. 120, p. 3819 (2008); Angew. Chem. Int. Ed. vol. 47, p. 3759 (2008)